Platelet Shp2 negatively regulates thrombus stability under high shear stress

• Published in: Journal of thrombosis and haemostasis Vol. 17; no. 1; pp. 220 - 231
• Main Authors: Hu, M., Liu, P., Liu, Y., Yue, M., Wang, Y., Wang, S., Chen, X., Zhou, Y., Zhou, J., Hu, X., Ke, Y., Hu, H.
• Format: Journal Article
• Language: English
• Published: England Elsevier Limited 01.01.2019
• Subjects: AKT protein; Animals; Blood clots; Blood Platelets - enzymology; Calcium-binding protein; Calmodulin; Calmodulin - blood; Collagen; Disease Models, Animal; Ferric chloride; Hemostasis; Homology; integrins; Mechanical stimuli; Mesenteric Vascular Occlusion - blood; Mesenteric Vascular Occlusion - enzymology; Mesenteric Vascular Occlusion - genetics; Mesenteric Vascular Occlusion - physiopathology; Mice, Knockout; Microfluidics; Occlusion; Perfusion; Phenotypes; Phosphorylation; platelet activation; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism; Platelets; Protein Binding; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - deficiency; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Protein-tyrosine-phosphatase; Proto-Oncogene Proteins c-akt - blood; Receptors, Thromboxane A2, Prostaglandin H2 - blood; Secretion; Shear stress; Shp2; Signal Transduction; Splanchnic Circulation; Stress, Mechanical; Thrombin; Thrombosis; Thrombosis - blood; Thrombosis - enzymology; Thrombosis - genetics; Thrombosis - physiopathology; Thromboxane A2; thromboxane A2; thrombus; Shp2; thromboxane A2; integrins; thrombus; platelet activation
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.14335

Essentials Shp2 negatively regulates thrombus stability under pathological shear rate. Shp2 suppresses TXA2 receptor‐mediated platelet dense granule secretion. Through αIIbβ3 outside‐in signaling, Shp2 targets calmodulin‐dependent activation of Akt. Shp2 may serve to prevent the formation of unwanted occlusive thrombi. Summary Background Perpetuation is the final phase of thrombus formation; however, its mechanisms and regulation are poorly understood. Objective To investigate the mechanism of Shp2 in platelet function and thrombosis. Methods and results We demonstrate that the platelet‐expressed Src homology region 2 domain‐containing protein tyrosine phosphatase Shp2 is a negative regulator of thrombus stability under high shear stress. In a ferric chloride‐induced mesenteric arteriole thrombosis model, megakaryocyte/platelet‐specific Shp2‐deficient mice showed less thrombi shedding than wild‐type mice, although their occlusion times were comparable. In accordance with this in vivo phenotype, a microfluidic whole‐blood perfusion assay revealed that the thrombi formed on collagen surfaces by Shp2‐deficient platelets were more stable under high shear rates than those produced by wild‐type platelets. Whereas Shp2 deficiency did not alter platelet responsiveness towards thrombin, ADP and collagen stimulation, Shp2‐deficient platelets showed increased dense granule secretion when stimulated by the thromboxane A2 analog U46619. Shp2 appears to act downstream of integrin αIIbβ3 outside‐in signaling, inhibiting the phosphorylation of Akt (Ser473 and Thr308) and dense granule secretion. Calmodulin was also shown to bind both Shp2 and Akt, linking Shp2 to Akt activation. Conclusions Platelet Shp2 negatively regulates thrombus perpetuation under high shear stress. This signaling pathway may constitute an important mechanism for the prevention of unwanted occlusive thrombus formation, without dramatically interfering with hemostasis.